Elicitation of antibodies against targets that are immunorecessive, cryptic, or transient in their native context is a challenge for vaccine design. One potential solution is precise immunogen design. The ability of structural biology to provide atomic-level detail of antibody-antigen interactions and of computational biology to manipulate protein structure has raised the possibility of replicating the antigenic surface recognized by a target antibody in silico. Recent successes in immunogen design by transplanting an epitope onto foreign scaffolds and in focusing the antibody response to a precise site using computational techniques such as scaffolding (also termed epitope-transplantation or antigenic resurfacing), highlights the notion that computational biology may play a crucial role in vaccine design. Rather than relying on a small set of well-defined tools, however, increasing evidence suggests that vaccine design will require the systematic development of computational algorithms, methods, and tools associated with the analysis, design and manipulation of protein structure. This also includes quaternary protein structure and protein-ligand interactions. Here we address a number of technological issues that are expected to impact structure-based vaccine design. Specifically, we describe the development of new protein design and structure-modeling algorithms, methods, and tools that are particularly suited for vaccine design.